CI: Blood Glucose Control (2009)

Treggiari MM, Karir V, Yanez ND, Weiss NS, Daniel S, Deem SA. Intensive insulin therapy and mortality in critically ill patients. Crit Care. 2008; 12(1): R29. Epub 2008 Feb 29.
PubMed ID: 18312617
Study Design:
B - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:

Investigate the effect of implementing a policy of tight glycemic control in a broader population of critically ill patients than previously studied, including a mix of trauma, surgical, neurological and medical intensive care unit (ICU) patients before and after introduction of intensive insulin protocols.

Inclusion Criteria:

First ICU stay during first hospitalization at one of seven ICUs in a tertiary care hospital.

Exclusion Criteria:
  • ICU stay fewer than 24 hours
  • ICU stay not completed before end of the study period during which a patient was admitted
  • Age younger than 16 years.
Description of Study Protocol:

Study population

A cohort of all patients admitted to one of seven ICUs at a tertiary care hospital over the course of a four-year period between March 1, 2001, and February 28, 2005.

Patients were classified by admitting ICU service:

  • Surgical
  • Medical
  • Coronary
  • Neurosurgical
  • Burn.

Patients were also classified by the type of admission:

  • Surgical
  • Medical.


Cohort divided into three periods corresponding to changing glycemic control goals and insulin therapy protocols:

  • Period 1=March 1, 2001, to February  28, 2002. During this period there was no specific glycemic control protocol; hyperglycemia was treated by a mix of subcutaneous and intravenous insulin, with a target blood glucose of 120mg per dL to 180mg per dL.
  • Period 2=March 1, 2002, to June 30, 2003. Target blood glucose of 80mg per dL to 130mg per dL.
  • Period 3=July 1, 2003, to Feb 28, 2005. Target blood glucose of 80mg per dL to 110mg per dL.


Insulin therapy to control blood glucose. [Study period was considered as a surrogate of intensive insulin therapy (IIT) and was used as the predictor of interest.]

Statistical Analysis

Primary outcome measures were defined a priori to be ICU and hospital mortality and analyzed using one-way analysis of variance or frequency tables as appropriate. Mortality probabilities were modeled using logistic regression for patients in each study period and to adjust for a priori-selected potential confounders.

Secondary safety outcome measures were:

  • Hypoglycemia at any time during the ICU stay (moderate hypoglycemia=less than 65mg per dL; severe hypoglycemia=less than 40mg per dL), was analyzed by logistic regression
  • Evidence of organ dysfunction measured by sequential organ failure assessment (SOFA) scores using the tobit model, a method that can deal with both discrete and continuous variables such as those that make up the SOFA score.

Confounders identified in the list below were analyzed using logistic regression as described above.

  • Severity of illness measured by simplified acute physiology scores (SAPS II) and the acute physiologic scores (APS) of the APACHE III score in the first 24 hours of ICU admission
  • Injury severity scores
  • Age
  • Race
  • Sex
  • Comorbidities as defined by SAPS II
  • Mechanical ventilation at ICU admission
  • History of diabetes.


Data Collection Summary:

Timing of Measurements

Blood glucose levels obtained closest to 6 a.m. were collected from central laboratory. For frequency of hypoglycemia, data were included from both central laboratory measures and point-of-care glucose testing.

Dependent Variables

  • ICU mortality
  • Hospital mortality
  • SOFA score
  • Occurrence of hypoglycemia.

Independent Variables

Blood glucose value (subjects divided into cohorts based on treatment protocol in effect during their ICU admission).

Description of Actual Data Sample:

Description of Actual Data Sample

Initial N

10,456 patients admitted to ICUs between March 2001 and February 2005:

  • Cohort 1 with no BG control (N=3,322), 1,467 (62%) male
  • Cohort 2 with BG target 80mg per dL to 130mg per dL (N=3,322), 2,071 (62.4%) male
  • Cohort 3 with BG target 80mg per dL to 110mg per dL (N=4,786), 3,044 (63.9%) male.


  • Cohort 1: 51.1 years±18.5 years
  • Cohort 2: 51.6 years±19.1 years
  • Cohort 3: 51.6 years±19 years.


70% white, 9% African-American, 6% Asian, 4% Hispanic, 2% Native American, 9% not known.


Harborview Medical Center, University of Washington School of Medicine, Seattle, WA.

Summary of Results:
  • IIT not associated with decreased ICU or hospital mortality
  • Four-fold increase in episodes of hypoglycemia with intensive insulin therapy
  • Trauma patients had higher ICU, but not overall hospital mortality with target glucose 80mg per dL to 110mg per dL

Multivariate Regression Analysis for Mortality and Instulin Treatment


Cohort 1: No BG Protocol


Cohort 2: Target Glucose 80mg/dL to 130mg/dL

OR (95% CI)

Cohort 3: Target Glucose 80mg/dL to 110mg/dL

OR (95% CI)

ICU mortality (entire population)



1.20 (0.98, 1.47)



1.26 (1.04, 1.53)



Hospital mortality (entire population)


1.11 (0.93, 1.31)



1.15 (0.98, 1.35)



ICU mortality (ICU LOS>3 days) 1.0

1.21 (0.95, 1.54)



1.14 (0.90, 1.44)



Hospital mortality (ICU LOS>3 days) 1.0

1.08 (0.87, 1.33)



1.01 (0.83, 1.24)



ICU mortality, trauma patients



1.25 (0.85, 1.84)


1.76 (1.23, 2.53)



Hospital mortality, trauma patients



1.12 (0.81, 1.54)


1.16 (0.85, 1.57)



Author Conclusion:

IIT in a mixed cohort of critically ill patients was not associated with a reduction in hospital mortality, and was associated with increased ICU and hospital mortality in some subgroups. Broad implementation of IIT may be premature, and additional randomized trials in diverse groups of critically ill patients are necessary.

Funding Source:
Roche Diagnostics Corporation (Indianapolis, IN, USA)
Pharmaceutical/Dietary Supplement Company:
Reviewer Comments:

Target glucose levels were never achieved. On average, blood glucose level was approximately 20mg per dL more than target range in each period.

Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) N/A
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? Yes
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? N/A
  4.1. Were follow-up methods described and the same for all groups? N/A
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) N/A
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? N/A
  4.4. Were reasons for withdrawals similar across groups? N/A
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? N/A
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) N/A
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? Yes
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? N/A
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? Yes
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
  6.6. Were extra or unplanned treatments described? N/A
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? N/A
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? N/A
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes